Epigenetic aberrations are a key driver of cancer pathogenesis. Long intergenic noncoding RNAs (lincRNAs) have emerged as a pervasive and important class of regulators that serve as the interface between DNA and chromatin modification machinery. The lincRNA HOTAIR is overexpressed in approximately a third of human breast carcinomas and is a powerful predictor of eventual metastasis and death. HOTAIR reprograms the breast cancer chromatin state to alter the positional identity of the cancer cells, enabling invasion and metastatic spread to distant organs. The long term goal of this project is to understand the mechanistic basis of lincRNA action in human cancers. First, using HOTAIR as a model system, we will address the structure-function relationship of a lincRNA and its oncogenic activities. Second, we will examine how HOTAIR targets specific genomic loci to relocalize Polycomb proteins. Third, we will determine whether HOTAIR may serve as a therapeutic target by testing its ongoing requirement during cancer progression. These experiments will provide key insights into how long noncoding RNAs may instigate cancer progression, and should pave the way for new cancer diagnostics and treatments in the future. ! PUBLIC HEALTH RELEVANCE: Breast cancer is the second most common cause of cancer death for women in the United States. These deaths are most often caused by the spread of breast cancer to other sites of the body. A new type of genes, termed long intergenic noncoding RNA (lincRNA) has been found to be important to promote breast cancer progression by increasing metastasis. Research into how lincRNAs change gene activities in breast cancer will help to improve the risk assessment of breast cancer patients and identify targets for cancer therapy.